Tangier disease

Definition

Tangier disease is a rare autosomal recessive condition characterized by low levels of high density lipoprotein cholesterol (HDL-C) in the blood, accumulation of cholesterol in many organs of the body, and an increased risk of arteriosclerosis.

Description

Donald Fredrickson was the first to discover Tangier disease. He described this condition in 1961 in a five-year-old boy from Tangier Island who had large, yellow-orange colored tonsils that were engorged with cholesterol. Subsequent tests on this boy and his sister found that they both had virtually no high density lipoprotein cholesterol (HDL-C) in their blood stream. Other symptoms of Tangier disease such as an enlarged spleen and liver, eye abnormalities, and neurological abnormalities were later discovered in others affected with this disease.

It was not until 1999 that the gene for Tangier disease, called the ABCA1 gene, was discovered. This gene is responsible for producing a protein that is involved in the pathway by which HDL removes cholesterol from the cells of the body and transports it to the liver where it is digested and removed from the body.

Cholesterol is transported through the body as part of lipoproteins. Low density lipoproteins (LDL) and high density lipoproteins (HDL) are two of the major cholesterol transporting lipoproteins. Cholesterol attached to LDL (LDL-C) is often called "bad" cholesterol since it can remain in the blood stream for a long time, and high levels of LDL-C can increase the risk of clogging of the arteries (arteriosclerosis) and heart disease. Cholesterol attached to HDL is often called "good" cholesterol since it does not stay in the blood stream for a long period of time, and high levels are associated with a low risk of arteriosclerosis.

Research as of 2001 suggests that the ABCA1 protein helps to transport cholesterol found in the cell to the surface of the cell where it joins with a protein called ApoA-1 and forms an HDL-C complex. The HDL-C complex transports the cholesterol to the liver where the cholesterol is digested and removed from the body. This process normally prevents an excess accumulation of cholesterol in the cells of the body and can help to protect against arteriosclerosis.

Genetic profile

Changes in the ABCA1 gene, such as those found in Tangier disease, cause the gene to produce abnormal ABCA1 protein. The abnormal ABCA1 protein is less able to transport cholesterol to the surface of the cell, which results in an accumulation of cholesterol in the cell. The accumulation of cholesterol in the cells of the body causes most of the symptoms associated with Tangier disease. The decreased efficiency in removing cholesterol from the body can lead to an increased accumulation of cholesterol in the blood vessels, which can lead to a slightly increased risk of arteriosclerosis and ultimately an increased risk of heart attacks and strokes. The ABCA1 protein defect also results in decreased amounts of cholesterol available on the surface of the cell to bind to ApoA-1 and decreased cholesterol available to form HDL-C. This in turn results in the rapid degradation of ApoA-1 and reduced levels of ApoA-1 and HDL-C in the bloodstream. It also leads to lower levels of LDL-C in the blood.

The ABCA1 gene is found on chromosome 9. Since we inherit one chromosome 9 from our mother and one chromosome 9 from our father, we also inherit two ABCA1 genes. People with Tangier disease have inherited one changed ABCA1 gene from their father and one changed ABCA1 gene from their mother, making Tangier disease an autosomal recessive condition.

Parents who have a child with Tangier disease are called carriers, since they each possess one changed ABCA1 gene and one unchanged ABCA1 gene. Carriers for Tangier disease do not have any of the symptoms associated with the disease, except for increased levels of HDL-C in their blood stream and a slightly increased risk of arteriosclerosis. The degree of risk of arteriosclerosis is unknown, and is dependent on other genetic and environmental factors, such as diet. Each child born to parents who are both carriers of Tangier disease has a 25% chance of having Tangier disease, a 50% chance of being a carrier, and a 25% chance of being neither a carrier nor affected with Tangier disease.

Demographics

Tangier disease is a very rare disorder with less than 100 cases diagnosed worldwide. Tangier disease affects both males and females.

Signs and symptoms

The symptoms of Tangier disease are quite variable but the most common symptoms of Tangier disease are enlarged, yellow-colored tonsils, an enlarged spleen, accumulation of cholesterol in the mucous membranes of the intestines, abnormalities in the nervous system (neuropathy), and an increased risk of arteriosclerosis. Less commonly seen symptoms are an enlarged liver, lymph nodes and thymus, and hemolytic anemia. Cholesterol accumulation has been seen in other organs such as the bone marrow, gall bladder, skin, kidneys, heart valves, ureters, testicles, and the cornea of the eye.

Symptoms involving the tonsils, intestines and spleen

The unusual appearance of the tonsils is due to an accumulation of cholesterol. Even when the tonsils are removed, small yellow patches at the back of the throat may be evident. The accumulation of cholesterol in the mucous membranes of the intestines results in the appearance of orange-brown spots on the rectum, and can occasionally result in intermittent diarrhea and abdominal pain. The enlargement of the spleen can result in anemia and decreased numbers of certain blood cells called platelets.

Nervous system abnormalities

Cholesterol can accumulate in the nerve cells which can result in nervous system abnormalities and symptoms such as loss of heat and pain sensation, weakness, increased sweating, burning prickling sensations, loss of feeling, eye muscle spasms, double vision, drooping eyelids, and decreased strength and reflexes. These symptoms can be mild to severe, and can be temporary or permanent. Most people with Tangier disease have some nervous system dysfunction, but in many cases the symptoms are mild and may be undetectable. Occasionally patients with Tangier disease experience progressive and debilitating nervous system abnormalities.

Arteriosclerosis

Since so few people are known to be affected with Tangier disease it is difficult to precisely predict their risk of developing arteriosclerosis and heart disease. Depending on their age, people with Tangier disease appear to have approximately four to six times increased risk for arteriosclerosis leading to heart disease. People over the age of 30 appear to have a six-fold increased risk. It is possible that Tangier patients are protected from higher risks of arteriosclerosis by lower than average levels of LDL-C in their blood stream.

Diagnosis

Tangier disease is diagnosed through assessment of clinical symptoms and biochemical testing. A diagnosis of Tangier disease should be considered in anyone with deposits of cholesterol on the cornea, an unexplained enlarged spleen or liver, or neurological abnormalities. Examination of the throat and tonsils and rectal mucous membrane should be performed on those suspected to have Tangier disease. Measurements of the total cholesterol, HDL-C, LDL-C, ApoA-1 and triglycerides should also be performed. Patients with Tangier disease have virtually no HDL-C in their bloodstream and ApoA-1 levels are reduced to one to three percent of normal. LDL-C levels are also reduced to approximately 40% of normal and triglyceride levels can be mildly elevated. As of 2001, DNA testing for Tangier disease is not available through clinical laboratories, although DNA testing on a clinical basis should be available in the future. Some laboratories may identify ABCA1 gene changes in patients as part of their research. Prenatal testing is only available if ABCA1 gene changes are identified in the parents.

Treatment and management

There is no treatment for Tangier disease and treatment of decreased HDL-C with medication is usually ineffective. Occasionally organs such as the spleen and tonsils are removed because of extensive accumulation of cholesterol. Arteriosclerosis may be treated through angioplasty or bypass surgery. Angioplasty involves inserting a small, hollow tube called a catheter with a deflated balloon through the groin or arm and into a clogged artery. The balloon is then inflated which enlarges the artery and compresses the blockage. Coronary artery disease can also be treated through bypass surgery, which is performed by taking a blood vessel from another part of the body and constructing an alternate path around the blocked part of the artery.

Prognosis

In most cases the prognosis for Tangier is disease is quite good. People who develop heart disease may, however, have a decreased lifespan depending on the severity of the disease and the quality of medical treatment.

Resources

BOOKS

Scriver, C. R., et al., eds. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill, 1995.

PERIODICALS

Brooks-Wilson, A., et al. "Mutations in ABCA1 in Tangier Disease and Familial High-density Lipoprotein Deficiency." Nature Genetics 22, no. 4 (August 1999): 336-345.

Oram, John. "Tangier Disease and ABCA1." Biochimica et Biophysica Acta 1529 (2000): 321-330.

ORGANIZATIONS

National Tay-Sachs and Allied Diseases Association. 2001 Beacon St., Suite 204, Brighton, MA 02135. (800) 906-8723. [email protected]. <http://www.ntsad.org>.

WEBSITES

"High Density Lipoprotein Deficiency, Tangier Type 1; HDLDT1." Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id+271900> (December 8, 1999).

Lisa Maria Andres, MS, CGC